Interventions for Persisting Ductus Arteriosus in the Preterm Infant

M. Obladen P. Koehne Interventions for Persisting Ductus Arteriosus in the Preterm Infant

M. Obladen (Editor) P. Koehne (Editor)

Interventions for Persisting Ductus Arteriosus in the Preterm Infant With 51 Figures and 7 Tables

123

Prof. Dr. Michael Obladen

Dr. Petra Koehne

Director, Department of Neonatology, Charité Universitätsmedizin Berlin, Campus Virchow/Campus Benjamin Franklin, Augustenburger Platz 1, 13353 Berlin [email protected]

Head Physician, Department of Neonatology, Charité Universitätsmedizin Berlin, Campus Virchow, Augustenburger Platz 1, 13353 Berlin [email protected]

ISBN 3-540-24511-1 Springer Medizin Verlag Heidelberg Cataloging-in-Publication Data applied for A catalog record for this book is available from the Library of Congress. Bibliographic information published by Die Deutsche Bibliothek Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data is available in the Internet at . This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer Medizin Verlag. Violations are liable for prosecution under the German Copyright Law. Springer Medizin Verlag. A member of Springer Science+Business Media springer.de © Springer Medizin Verlag Heidelberg 2005 Printed in The Netherlands The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publisher cannot guarantee the accuracy of any information about dosage and application thereof contained in this book. In every individual case the user must check such information by consulting the relevant literature. SPIN 11384281 Cover Design: deblik, Berlin, Germany Typesetting: TypoStudio Tobias Schaedla, Heidelberg, Germany Printed on acid free paper

18/3160/yb – 5 4 3 2 1 0

V

Preface »Nature knows in advance that the fetal lung, an organ in development and without movement, does not have the same needs as the mature, breathing lung. Nature has therefore connected the pulmonary artery with the aorta.« This was written by Galen in the second century after Christ , confirmed by Giulio Cesare Aranzio <de humano foetu> in 1564 and later falsely attributed to Leonardo Botallo who became famous by this error. By connecting the pulmonary artery with the aorta, nature had not foreseen that in Europe most infants born at 25–27 weeks gestation would survive at the beginning of the 21st century. Over the past few years we have witnessed a remarkably rapid evolution in the professional level of neonatology and in the survival of immature infants. Sadly, many of these survivors later have neurodevelopmental handicaps, and presently there is not too much the neonatologist can do to prevent them. Avoiding ventilation, pneumothorax, and hypocarbia are the best choice. Closure of the ductus is another option, but many uncertainties exist concerning indication, approach, best time, and side effects. These issues were discussed in a European workshop in Fulda, Germany, on April 4 and 5, 2004. Not only the speakers but most participants were experts either in neonatology or in pediatric cardiology, and this small book contains the abstracts of the workshop, which, as we hope, will help to define the level of evidence and to develop standards of intervention for persisting ductus arteriosus in Europe. With survival of more and more immature infants, adequate dealing with the ductus will become a challenge for every perinatal center. We are deeply indebted to the many talented and dedicated contributors, we thank the staff of Springer publishers for good advice and for help in editing this volume, and we thank Dr. Barbara Donnerstag and Mr. Eberhard Kroll from Orphan Europe, not only for sponsoring this meeting but also for developing evidence based therapies for specific and small patient groups in whom little money can be earned. Berlin, December 2004

Michael Obladen, MD Petra Koehne, MD

VII

Table of Contents Part I: Basics 1

Part II: Clinical Features

Developmental Anatomy of the Ductus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

6

Regina Bökenkamp Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Embryogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ductal Maturation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Patent Ductus Arteriosus in Premature Infants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Persistent Ductus Arteriosus (PDA) . . . . . . . . . . . . . . Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

Walter Kachel 2 2 2

Association with Pulmonary Immaturity / Surfactant Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . 26 Association with Pulmonary Infection / Inflammatory Response . . . . . . . . . . . . . . . . . . . . . . . 26 X-Ray Opacities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 PDA, Lung Water, and Pulmonary Hemorrhage . . 27 Lung Mechanics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 Surfactant Substitution . . . . . . . . . . . . . . . . . . . . . . . . 28 Chronic Lung Disease . . . . . . . . . . . . . . . . . . . . . . . . . 28 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

4 4 4 4

Regulation of Smooth Muscle Contraction . . . . 6 Ingo Morano References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10

3

7

Prostaglandin Metabolism and Effects of Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Mesenteric Perfusion . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Patent Ductus Arteriosus and Mesenterial Perfusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31 Necrotizing Enterocolitis . . . . . . . . . . . . . . . . . . . . . . 31 Patent Ductus Arteriosus and Necrotizing Enterocolitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 Indomethacin Intervention . . . . . . . . . . . . . . . . . . . . 33 Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Indomethacin Versus Ibuprofen . . . . . . . . . . . . . . . 33 Surgical Ligation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Postnatal Circulatory Adaptation . . . . . . . . . . . . 15 Michael Hofbeck References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

5

Epidemiology of Persisting Ductus in Preterm Infants . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Christiane Pees, Michael Obladen Congenital Anomaly or Prolonged Adaptation? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 Clinical Relevance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Frequency Depends on Immaturity and Echocardiography . . . . . . . . . . . . . . . . . . . . . . . . 20 Individual Variability . . . . . . . . . . . . . . . . . . . . . . . . . . 20 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Influence on Mesenteric Perfusion and Necrotizing Enterocolitis . . . . . . . . . . . . . . . . 31 Josef Sonntag

Karsten Schrör

4

Persisting Ductus Arteriosus and Respiratory Problems . . . . . . . . . . . . . . . . . . 26

8

Persisting Ductus Arteriosus and Intraventricular Hemorrhage . . . . . . . . . . . . . . . . 35 Rolf F. Maier Cerebral Perfusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 PDA, Lung Maturity, and IVH . . . . . . . . . . . . . . . . . . . 35 Pharmacological Interventions . . . . . . . . . . . . . . . . 36 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

VIII

Table of Contents

Part III: Diagnostics

13 Comparison of Indomethacin and Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Bart van Overmeire

9 Echocardiographic Assessment . . . . . . . . . . . . . . 40 Helmut Singer References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 10 Cerebral Doppler Sonographic Measurements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Properties of Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . 65 Therapy and Prophylaxis of Patent Ductus Arteriosus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Effects on Regional Circulation . . . . . . . . . . . . . . . . 67 Pharmacokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Karl-Heinz Deeg, Burkhard Trusen Intracranial Arteries . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Doppler Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 PDA-Specific Flow Patterns . . . . . . . . . . . . . . . . . . . . 46 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Part IV: Interventions 11 Therapeutic Options . . . . . . . . . . . . . . . . . . . . . . . . 52 Axel von der Wense Prevention of PDA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Prophylactic Administration of Cyclooxygenase Inhibitors . . . . . . . . . . . . . . . . . . . . . 53 Indomethacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Hamburg Ibuprofen Study . . . . . . . . . . . . . . . . . . . . . 54 Current Hamburg Concept of PDA Treatment . . 56 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

12 Surgical Closure . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Michael Hübler History . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Transport to the Operating Room . . . . . . . . . . . . . . 57 Preparation for Operation in the NICU . . . . . . . . . 58 Perioperative Management . . . . . . . . . . . . . . . . . . . . 58 Surgical Management . . . . . . . . . . . . . . . . . . . . . . . . . 58 Postoperative Management . . . . . . . . . . . . . . . . . . . 60 Complications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Outcome and Complications in our Center . . . . . 63 Minimally Invasive Approaches . . . . . . . . . . . . . . . . 63 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

14 Indomethacin Effects and Side Effects . . . . . . . 69 Berndt Urlesberger Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 Management of Symptomatic PDA . . . . . . . . . . . . 69 Management of Asymptomatic PDA . . . . . . . . . . . 69 Prophylactic Indomethacin . . . . . . . . . . . . . . . . . . . . 70 Conclusions Regarding Effects . . . . . . . . . . . . . . . . . 70 Side Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 Impairment of Renal Function . . . . . . . . . . . . . . . . . 70 Impairment of Cerebral Perfusion . . . . . . . . . . . . . . 70 Abdominal Side Effects . . . . . . . . . . . . . . . . . . . . . . . . 71 Interference With Blood Glucose . . . . . . . . . . . . . . 71 Platelet Dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Contraindications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72

15 Complications of Cyclooxygenase Inhibition in Preterm Infants . . . . . . . . . . . . . . . . 74 Véronique Gournay Pharmacology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Cerebral Effects of COX Inhibitors . . . . . . . . . . . . . 75 Pulmonary Effects of COX Inhibitors . . . . . . . . . . . 75 Renal Effects of COX Inhibitors . . . . . . . . . . . . . . . . . 78 Intestinal Effects of COX Inhibitors . . . . . . . . . . . . . 78 Effect of Ibuprofen on Bilirubin-Albumin Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

IX Table of Contents

16 Ibuprofen in Infants below 28 Gestational Weeks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84

Part V: Perspectives

Petra Koehne The Timing of PDA Intervention . . . . . . . . . . . . . . . . 84 Parameters Characterizing the HemoDynamic Significance of a PDA . . . . . . . . . . . . . . . . 85 Early Ibuprofen for Symptomatic PDA in Infants under 28 Weeks Gestational Age . . . . . . . 85 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91

17 Intravenous Ibuprofen: State of Registration . . . . . . . . . . . . . . . . . . . . . . . . 92 Marie Christine Fortun

18 Summary and Perspectives . . . . . . . . . . . . . . . . . 94 Michael Obladen Basics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 Diagnostics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Indomethacin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Ibuprofen . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98

X

List of Contributors Dr. Regina Bökenkamp

Prof. Dr. Walter Kachel

Prof. Dr. Karsten Schrör

Department of Anatomy and Embryology, Leiden University Medical Center, Wassenaarsenweg 62, Postbox 9602, 2300, RC Leiden, The Netherlands

Director, Department of Pediatrics/ Perinatalzentrum, SLK-Kliniken Heilbronn GmbH, Am Gesundbrunnen 18–20, 74067 Heilbronn, [email protected]

Director, Institute for Pharmacology and Clinical Pharmacology, Heinrich-Heine-Universität, Universitätsstr. 1, 40225 Düsseldorf, [email protected]

Prof. Dr. Karl-Heinz Deeg

Dr. Petra Koehne

Director, Children’s Hospital, Klinikum Bamberg, Buger Straße 80, 96049 Bamberg, [email protected]

Head Physician, Department of Neonatology, Charité Universitätsmedizin Berlin, Campus Virchow, Augustenburger Platz 1, 13353 Berlin, [email protected]

Director, Department of Pediatric Cardiology, Klinik für Kinder und Jugendliche der Universität Erlangen-Nürnberg, Loschgestr. 15, 91054 Erlangen, htsinger@ kinder.imed.uni-erlangen.de

Prof. Dr. Rolf F. Maier

PD Dr. Josef Sonntag

Director, Department of Neonatology and Pediatric Neurology, Klinikum der Philipps-Universität Marburg, Deutschhausstr. 12, 35033 Marburg, [email protected]

Department of Pediatrics, Städtisches Klinikum Lüneburg, Bögelstraße 1, 21339 Lüneburg, josef.sonntag@ klinikum-lueneburg.de

Prof. Dr. Helmut Singer

Dr. Marie-Christine Fortun Regulatory Affairs Director, Orphan Europe (France) SARL, Immeuble »Le Wilson«, 70, avenue du General de Gaulle, F92058 Paris, France, [email protected]

Dr. Véronique Gournay Division of Pediatric Cardiology, University Hospital of Nantes, Hôpital Mère Enfant, 7, quai Moncousu, 44093 Nantes Cedex 1, France, [email protected]

Prof. Dr. Michael Hofbeck Director, Division of Pediatrics II, Universitätsklinikum Tübingen, Hoppe-Seyler-Straße 3, 72070 Tübingen, michael.hofbeck@ med.uni-tuebingen.de

Dr. Michael Hübler Attending Surgeon, Department of Cardiothoracic and Vascular Surgery, German Heart Institute Berlin, Augustenburger Platz 1, 13353 Berlin, [email protected]

Prof. Dr. Ingo Morano Director, Division of Molecular Muscle Physiology, Max-Delbrück-Center Berlin, Robert-Rössle-Straße 10, 13092 Berlin, [email protected]

Prof. Dr. Michael Obladen Director, Department of Neonatology, Charité Universitätsmedizin Berlin, Campus Virchow/ Campus Benjamin Franklin, Augustenburger Platz 1, 13353 Berlin, [email protected]

Dr. Burkhard Trusen Head Physician, Children’s Hospital, Klinikum Bamberg, Buger Straße 80, 96049 Bamberg, [email protected]

Prof. Dr. Berndt Urlesberger Department of Neonatology, Universitätsklinik für Kinder- und Jugendheilkunde, Auenbrugger Platz 30, A-8036 Graz, Austria, [email protected]

Prof. Dr. Bart van Overmeire Department of Pediatrics, Division of Neonatology, University Hospital of Antwerp, Wilrijkstreet 10, B-2650 Edegem, Belgium, [email protected]

Dr. Christiane Pees Department of Congenital Heart Defects, German Heart Institute Berlin, Augustenburger Platz 1, 13353 Berlin, [email protected]

Dr. Axel von der Wense Department of Neonatology and Pediatric Intensive Care, Altonaer Kinder-Krankenhaus, Bleickenallee 38, 22763 Hamburg, [email protected]

XI

List of Abbreviations BPD CBF CI CLD CHD COX ELBW IVH MHC MLC MLCK NEC NICU NNT NO NSAID OR PaO2 PCO2 PGE2

Bronchopulmonary dysplasia Cerebral blood flow confidence interval Chronic lung disease Congenital heart defect Cyclooxygenase (isoforms -1 and -2) Extremely low birth weight ( 1.4, (2) reduction in diastolic flow in the anterior cerebral artery (resistance index > 0.8), or (3) respiratory step back (increased oxygen supply > 15% = required FiO2 > 0.36). Main exclusion criteria were: ductus-dependent cardiopathy, right-to-left shunt through the PDA, severe intra-ventricular hemorrhage (Papile grade III or IV) or thrombocytopenia < 50.000/nl. Intravenous ibuprofen was started after confirmation of a hemodynamically significant PDA with 10 mg/kg body weight and was continued with two doses of 5 mg/kg in 24 h intervals, infused continuously over 15 minutes. Besides determination of a hemodynamically significant PDA echocardiographic measurements included the following parameters for the evaluation of pulmonary vascular resistance: shunt direction and flow velocity via the ductus

and foramen ovale, estimation of the right systolic ventricular pressure (RSVP) in the presence of tricuspid regurgitation (TR) and systolic pulmonary artery pressure (⊡ Figs. 16.2 and 16.3). Cerebral ultrasound and echocardiography were performed daily in the 29 preterm infants until 72 h of life. In the treated infants these measurements were obtained during the first ibuprofen administration, just before the second dose and 24 h after the third dose. During every ibuprofen infusion pre-ductal (right upper limb) and post-ductal (left upper or lower limb) oxygen saturation was recorded continuously to rule out occurrence of right-to-left ductal shunting, evident by a sudden increase of the maximal saturation difference. Of the 29 screened patients 14 were excluded from the study: 3 patients with severe IVH, 3 with pulmonary hypertension, and 8 due to nonrelevant PDA (⊡ Fig. 16.4). Among the 15 treated infants 8 showed tricuspid regurgitation before the first ibuprofen dose with an estimated pulmonary vascular pressure below systemic systolic

89 Early Ibuprofen for Symptomatic PDA in Infants under 28 Weeks Gestational Age

16

⊡ Fig. 16.2 Schematic diagram of the heart during echocardiography in the apical position. To obtain the apical fourchamber view, the transducer is placed above the apex of the heart along an axis from the left shoulder to the right mammilla. This view allows evaluation of the atrial and ven-

tricular septa, atrial and ventricular chambers, AV valves, and pulmonary veins, as well as identifying tricuspid regurgitation, when present. LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle; TV, tricuspid valve; MV, mitral valve; IVS, interventricular septum; IAS, interatrial septum.

⊡ Fig. 16.3 Color doppler echocardiography in the apical fourchamber view. The blue color coded blood flow represents the presence of tricuspid regurgitation (left). Estimation of the systolic pulmonary artery pressure is most accurately obtained

from the peak velocity of the tricuspid regurgitation (TR Vmax, green color coding). In this example (right) TR Vmax was 310 cm/second and estimated right ventricular systolic pressure (RVSP) 43 mmHg (including 5 mmHg central venous pressure).

90

Chapter 16 · Ibuprofen in infants Below 28 Gestational Weeks

pressure (⊡ Table 16.2). This elevation of pulmonary pressure did not increase above supra-systemic levels and instead resolved during ibuprofen administration. PDA closure rate 24 h after the third ibuprofen dose was 53.3% in the treatment group. The closure rate is comparable to that described by others (Van Overmeire 2000). Detailed echocardiographic and pharmacokinetic data will be published elsewhere.

Conclusion Curative treatment with ibuprofen for a hemodynamically significant patent ductus arteriosus in preterm infants below 28 weeks GA was not associated with the occurrence of pulmonary hypertension when it was administered beyond 24 h of life and after prior echocardiographic exclusion of supra-systemic pulmonary hypertension.

⊡ Fig. 16.4 Study population. Infants screened and studied (left) and outcome of ibuprofen treatment (right). PPHN, persistent pulmonary hypertension.

⊡ Table 16.2 Tricuspid regurgitation (TR) with an estimated pulmonary vascular pressure (RVSP median 31 mmHg; range 23 – 43 mmHg) below systemic systolic pressure (median 41 mmHg; range 32 – 51 mmHg) in 8 patients of the therapy group before the first ibuprofen dose.

16

TR Vmax [cm/s]

RVSP mmHg [incl. 5 mmHg ZVD]

systolic blood pressure [mmHg]

260

32

41

290

39

45

210

23

32

240

28

37

260

32

44

250

30

38

250

30

41

310

43

51

91 References

References Evans N, Iyer P: Assessment of ductus arteriosus shunting in preterm infants requiring ventilation: effect of inter-atrial shunting. J Pediatr 1994; 125: 778–85. Evans N, Malcolm G, Osborn D, Kluckow M: Diagnosis of patent ductus arteriosus in preterm infants. Neo Reviews 2004; 5: e86–e97 Gournay V, Savagner C, Thiriez G, Kuster A, Rozé J-C: Pulmonary hypertension after ibuprofen prophylaxis in very preterm infants. Lancet 2002; 359: 1486–88. Johnson GL, Breart GL, Gewitz MH, Brenner JI, Lang P, Dooley KJ, Ellison RC: Echocardiographic characteristics of premature infants with patent ductus arteriosus. Pediatrics 1983; 72: 864–71. Kluckow M, Evans N. Early echocardiographic prediction of symptomatic patent ductus arteriosus in preterm infants requiring mechanical ventilation. J Pediatr 1995; 127: 774–79. Kluckow M, Evans N. Ductal shunting, high pulmonary blood flow, and pulmonary hemorrhage. J Pediatr 2000; 137: 68–72. Kluckow M, Evans N. Superior vena cava flow in newborn infants: a novel marker of systemic blood flow. Arch Dis Child Fetal Neonatal Ed 2000; 82: F188–F187. Kluckow M, Evans N. Low superior vena cava flow and intraventricular haemorrhage in preterm infants. Arch Dis Child Fetal Neonatal Ed 2000; 82: F182–F194. Koehne PS, Bein G, Alexi-Meskhishvili V, Weng Y, Bührer C, Obladen M: Patent ductus arteriosus in very low birthweight infants: complications of pharmacological and surgical treatment. J Perinat Med 2001; 29: 327–34.

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Mandelbaum Isken VH, Linderkamp O: Cardiac output by pulsed Doppler in neonates using the apical window. Pediatr Cardiol 1991; 12: 13–6. Mellander M, Larsson LE, Ekström-Jodal B, Sabel KG: Prediction of symptomatic patent ductus arteriosus in preterm infants using Doppler and M-mode echocardiography. Acta Paediatr Scand 1987; 76: 553–559. Osborn DA, Evans N, Kluckow M: Hemodynamic and antecedent risk factors of early and late periventricular/intraventricular hemorrhage in premature infants. Pediatrics 2003; 112: 33–39. Patel J, Roberts I, Azzopardi D, Hamilton P, Edwards AD: Randomized double- blind controlled trial comparing the effects of ibuprofen with indomethacin on cerebral hemodynamics in preterm infants with patent ductus arteriosus. Pediatr Res 2000; 47: 36–42. Sahn DJ, DeMaria A, Kisslo J, Weyman A: Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978; 58: 1072–83. Skelton R, Evans N, Smythe J: A blinded comparison of clinical and echocardiographic evaluation of the preterm infant for patent ductus arteriosus. J Paeds Child Health 1994; 30: 406–11. Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J, Degroote K, Langhendries JP: A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000; 343: 674–81. Yeh TF, Achanti B, Patel H, Pildes RS: Indomethacin therapy in premature infants with patent ductus arteriosus – determination of therapeutic plasma levels. Dev Pharmacol Ther 1989; 12: 169–78.

17 Intravenous Ibuprofen: State of Registration Marie Christine Fortun

The European Commission granted an orphan designation for ibuprofen in the indication of treatment of patent ductus arteriosus (PDA) in February 2001 (registered as n° EU/3/01/20 in the European Register of Orphan Medicinal Products). Registration is planned under the trade name Pedea®. At that time, the COMP (Committee of Orphan Medicinal Products) located at the EMEA in London estimated the prevalence of the condition as being 2.13 in 10,000 persons. PDA is a rare disorder. As no appropriate formulation of ibuprofen was available, there was an unmet medical need. Therefore, Orphan Europe, specialized in orphan drugs, decided more than 6 years ago to develop an appropriate formulation of ibuprofen to treat premature infants safely and efficiently. This would lead to the first intravenous formulation of ibuprofen. Pharmaceutical development work linked to the route of administration was performed. Special requirements were needed such as dedicated facilities and sterile atmosphere. Even though the toxicological profile of ibuprofen was already known for more than 40 years, Orphan Europe put in place additional studies related to the target population and the route of administration. The following animal studies were conducted: ▬ A local tolerance study conducted in rabbits comparing ibuprofen to placebo, using the iv route.

▬ An acute toxicity study using the iv route in newborn rats comparing the effects of ibuprofen, saline solution and placebo. Therefore after compilation of all the data, an application for marketing authorization was submitted to the European Agency (EMEA) in May 2003. The European registration of Pedea® is currently on-going using the so-called centralized procedure (driven by Ireland acting as rapporteur and the UK acting as co-rapporteur). The CPMP (scientific committee responsible for the evaluation of quality, safety and efficacy of medicinal products submitted for registration) located at the EMEA has now released a positive opinion towards the registration (on 22 April 2004). The European marketing authorization, applicable in the 25 countries of the enlarged European Union, is expected during summer (August 2004). The therapeutic indication will be: »Pedea® is indicated for the treatment of hemodynamically significant patent ductus arteriosus in preterm newborn infants of less than 34 weeks of gestational age«. Pedea® will be presented as a box of 4 ampoules of 2ml containing 5mg/ml of ibuprofen.

V

Part V Perspectives Chapter 18 Summary and Perspectives – 94 Michael Obladen

18 Summary and Perspectives Michael Obladen

A major conclusion of the Fulda conference was that there is no clear definition of clinically relevant ductus arteriosus in the preterm infant. Even more worrisome is the fact that, despite a high rate of activities, little or no long-term benefit has been established for ductus oriented interventions.

Basics Related to better definitions, terminology should be clarified: Prolonged – patent – persisting ductus are not clearly distinguishable. Anatomically, persisting is different from patent ductus, as no separation of endothelium from the basal lamina occurs. During the phase of ductal closure, cushion formation is essential. Preterm infants vary from one to the other, and little is known about those 50% of immature infants in whom the ductus closes easily and spontaneously. PDA is associated with respiratory distress syndrome. However, at least in some infants, inflammatory mechanisms contribute to reopening of the ductus. Both COX-1 and COX-2 are required to close the ductus arteriosus functionally. Interventions must act on both tonic and phasic components of contraction. Besides prostaglandins, nitric oxide and endothelin-1 are involved in ductus contraction. Little is known about prostaglandin metabolism after indomethacin or ibuprofen

treatment. The role of angiogenic factors, such as vascular endothelial growth factor (VEGF) involved in the definitive ductal closure, as well as their interaction with the cyclooxygenase and prostaglandin pathways, remains to be clarified. Following birth, transitional circulation with right-to-left shunting persists in some infants for hours, which fails to establish and maintain low pulmonary resistance. During this phase ductus intervention is unfavorable. Consequences for practice: Antenatal glucocorticoid administration reduces the risk for PDA. Implications for research: Either exogenous (e.g. anti-inflammatory) or endogenous (e.g. genetic polymorphisms) mechanisms must be present, the knowledge of which will improve understanding of PDA pathophysiology and may help to develop strategies to prevent PDA. The interaction of oxygen, nitric oxide, endothelin, and prostaglandins during the initial phase of ductal closure as well as the role of angiogenic factors during remodelling and obliteration of the ductus need to be further addressed.

Clinical Features PDA is associated with respiratory failure, but no causal relation to BPD has been established. PDA compromises mesenteric perfusion, is associated

95 Indomethacin

with NEC, and early closure may decrease NEC risk. No causal relation of indomethacin and NEC has been established. PDA and intraventricular hemorrhage are associated but a causal relation has not been established. Prophylactic early indomethacin, but not late treatment of symptomatic PDA has been shown to prevent intraventricular hemorrhage. Most randomized controlled trials had a backup treatment option, and most are 10–25 years old. Long-term benefit of PDA intervention has never been established by randomized controlled trials. Consequences for practice: IVH prevention and PDA closure can be achieved with prophylactic indomethacin administration. Especially when performed in the first 12 hours of life, rightto-left shunting and pulmonary hypertension must be ruled out before this approach is chosen. The prophylacic approach, however, is devaluated by the fact that many infants will unnecessarily receive a potentially toxic drug. Implications for research: To demonstrate benefit for treatment of symptomatic PDA, randomized controlled trials with untreated controls and with a longterm neurodevelopmental outcome still are needed.

Diagnostics There is no satisfactory definition of relevant PDA and an urgent need for predictors indicating which infant will be harmed by the ductus and will benefit from PDA intervention. Before any PDA intervention, echocardiography should be performed to exclude PDA dependent heart malformation, and, perhaps more important, to exclude transitory circulation with right-to-left shunting. As decisions must be reached within a relatively short time and around the clock, neonatologists must be familiar with echocardiography – at least to such a degree that they can evaluate size and shunt direction of the ductus arteriosus. Echocardiography has been widely used to define hemodynamic »significance« of the PDA, but turns out to be a two edged sword with the inherent risk to overdiagnose and overtreat ductuses in a prolonged but physiological phase of

18

postnatal adaptation. Anatomic measurements (LA, LV size) indicate cardiac failure more reliably than LA/Ao ratio. Ductus diameter can be easily measured with color Doppler and seems to be more reliable than flow rate (Qp/Qs). It is the large ductus which will fail to close spontaneously, but the optimal threshold limit is unknown. A diameter of 3mm is surely relevant, but what about 2 mm? Brain perfusion ist best measured by Doppler flow in ICA or ACA; time averaged flow velocity (TAV) or absent or negative enddiastolic flow (Ved) is more valuable than resistance index (RI), which may be influenced by the pressure exerted on the transducer. Consequences for practice: The diagnosis of a relevant PDA should not be based on sonographic findings alone. Especially in stable infants, neonatologists should mistrust echocardiographic indicators of hemodynamic significance. Brain perfusion should be assessed by time averaged or enddiastolic flow velocity instead of resistance index. Implications for research: With highly standardized echocardiography, fluid administration, and oxygenation, reference values for ductus closure and diameter should be obtained in both stable preterm infants and those with RDS, but without PDA intervention.

Indomethacin Indomethacin is registered in the US, but not in all European countries. For indomethacin, more studies are available and the evidence regarding its effects is higher. Side effects are renal failure, reduced CBF, intestinal hypoperfusion, but not NEC. Renal failure may be severe, but is usually reversible during several days after discontinuation of treatment. Preventive use of indomethacin has been found to be effective in reducing the incidence of cerebral hemorrhage. This effect, however, has not been established for curative treatment in symptomatic PDA. Consequences for practice: Most frequently used dosages are 0.1–0.2 mg/kg, repeated after 12–24 hours for a maximum of 3–6 doses. When

96

Chapter 18 · Summary and Perspectives

renal failure, pulmonary hypertension, acute bleeding, or thrombocytopenia are present, indomethacin is contraindicated and surgery represents a safer option. Implications for research: The optimal administration schedule and duration of the treatment need to be clarified by controlled trials.

Implications for research: Highest priority must be given to ibuprofen safety concerning the brain. As unbound bilirubin is difficult to measure in vivo, brain stem acoustic potentials may help to recognize if there is clinically relevant bilirubin toxicity during ibuprofen treatment.

Surgery Ibuprofen

18

With the European registration of ibuprofen a complicated situation arises: A new drug is registered despite the absence of extensive efficacy and safety studies, whereas the well studied indomethacin is not registered in most countries. Ibuprofen has two enantiomers, the S form with serum half life of 26 hours and the R form with serum half life of 10 hours. Two different galenic preparations of ibuprofen have been used, ibuprofen lysine and ibuprofen THAM, and it is unknown whether there are differences in the action of these two preparations. Most studies have used ibuprofen lysine rather than THAM, which is the registered formula. Ibuprofen causes less circulatory disturbance and less oliguria than indomethacin. However, reduced incidence of intraventricular hemorrhage (as established for indomethacin) has not yet been shown for ibuprofen. Severe pulmonary hypertension has been observed in three infants when used during the first six hours of life, but not in infants >24 hours of age, in whom right-to-left shunting had been excluded. Ibuprofen has been shown to displace bilirubin from albumin at high serum levels, which places the immature brain at risk for kernicterus especially in jaundiced infants. Amikacin half-life is prolonged by ibuprofen. What about other aminoglycosides, e.g. gentamicin? Ibuprofen decreases neutrophil apoptosis and the clinical significance of this finding for infants treated during infection is unclear. Consequences for practice: Don’t run to the drugstore – yet. Benefits and risks of ibuprofen are poorly known, and presently the drug should be used only in controlled clinical trials. Most frequently studied dosage was initial 10 mg/kg, followed by two dosages of 5 mg/kg every 24 hours.

PDA clipping by the cardiac surgeon in the NICU has been the treatment of choice in infants, in whom pharmacotherapy failed. Operation in the NICU avoids the severe problems associated with transfer of an unstable infant. However, many of these infants had severe brain problems. It is probable that the most immature and sickest infants were those ligated, and it may well be that prolonged PDA and not the surgical intervention itself caused the problems. Some concern, however, remains. Surgery associated complications include pneumothorax, vocal palsy, and thoracic deformity. Catheter interventions are not available for preterm infants, and, due to the risks of cardiac catheterization in infants under 1000 g birthweight, also are not likely to be developed for this population. In most centers minimally invasive thoracoscopic techniques presently are devaluated by the need for transfer to the operation room. Consequences for practice: Elaborate organization provided, thoracotomy can be performed safely in the neonatal intensive care unit and is preferable to the transfer of the ventilated infant to the operating room. Prophylactic insertion of a pleural catheter helps to minimize the risk of postoperative pneumothorax. Implications for research: In appropriate setting and design, randomized controlled trials may clarify if there is a benefit of video assisted thoracoscopic versus conventional surgery. If the technique is shown to have significant advantages over thoracotomy, mobile equipment must be developed to avoid transfer of the unstable infant.

97 Perspectives

Perspectives Research is warranted into more physiologic approaches to prevent or treat PDA. Presently, there is no consensus regarding adequate oxygenation, fluid intake, or incubator versus open radiant heater care – all three being factors associated with persistence of ductus arteriosus. In order to understand safety and risks of the two cyclooxigenase inhibitors, large head-to-head

18

trials with long-term endpoints are needed. If efficacy and benefit for the quality of life are to be studied, an untreated control group is required, possibly with a late emergency rescue escape arm. Endpoints in these trials will be difficult to define, but certainly should include standardized neurodevelopmental testing, assessment of hearing threshold, chronic lung disease, and renal function at an age of at least two years.

Subject Index

A abdominal side effects 71 actin 6 actomyosin complex 6 ADH (antidiuretic hormone) 70 administration, route of 92 albumin-bilirubin binding 81–82 anesthesia 58 anatomy, developmental 2–5 antenatal glucocorticoids 17, 52, 94 antidiuretic hormone (ADH) 70 aorta / aortic – circulation, aortic 40 – descending aorta 3, 41, 60 – root, aortic (see there) 40, 43, 84–85 – shunt, aorto-pulmonary 48 – valve, aortic 42 arachidonic acid 13 artery / arteries / arterial (A.) – A. basilaris 47 – A. cerebri anterior 40, 45, 47, 79, 84–86 – A. cerebri medialis 47 – A. lusoria 40 – A. renalis 40, 70

– carotid artery 41, 45 – Heubner’s artery 45 – intracranial 46–47 – mesenteric artery 46, 71, 79–81 – pulmonary artery 3, 41–42, 88 atrium / atrial – atrioventricular valve 42, 89 – enlargement, atrial 40 – left atrium 40, 42–43, 84–85, 89 – right atrium 40, 42, 89 – septum, interatrial 89 autoregulation – cerebral blood flow 35–36, 75

B bilirubin – albumin binding 81–82 – encephalopathy (kernicterus) 81 – serum concentration 82 bleeding (see also hemorrhage) 12, 35–38, 52, 72 – abnormal bleeding 72 blood flow – autoregulation 75 – cerebral (see there) 35–36, 67, 70, 75, 85

– color Doppler 40 – gastrointestinal 74 – mesenterial 33, 54, 79 – pulmonary 28, 75, 77 – renal (RBF) 54, 70, 78 – systemic, upper body 87 – velocity 33, 71 blood gas analysis 60 blood pressure 60 blood glucose level 58, 70–71 blood volume, cerebral 67, 75 bowel – ischemia 79 – perforation 71, 78–79 brain (see also cerebral) – development 75 – perfusion 12, 46, 70, 75 branchial arches 3 bronchopulmonary dysplasia (BPD) 28, 52, 69

C calmodulin 7–8 carbon dioxide tension, cardiac output 15, 77 cardiomegaly 27

58, 75

99 Subject Index

cardiopulmonary adaptation 15–18, 78 carotid artery (see artery, c.) 41, 45 catheter interventions 60 – pleural 60 cerebral (see also brain) – artery 40, 45, 47, 79, 84–85 – autoregulation 35–36 – blood flow (CBF) 35–36, 67, 70, 75 – blood volume 67, 75 – circulation 67, 76 – Doppler sonographic measurements 45–49, 86 – flow variation 46, 85 – hemodynamics 75 – hemorrhage, intracerebral 35–37, 52, – oxygen / oxygenation 67, 71, 74–75 – palsy (CP) 37, 70 – perfusion (see there) 12, 70–71, 85 – vascular resistance 80 chambers, heart (see ventricles) 89 Char syndrome 4 chest deformity 63 circulation – aortic 40 – cerebral 67, 76 – ductus-dependent 41 – fetal 15–16 – gastrointestinal 67–68 – peripheral 45 – pulmonary 40, 45 – systemic 40, 45 – transitional 15, 94–95 circulatory adaptation, postnatal 15–18 CLD (chronic lung disease) 28–29, 69 clinical symptoms of PDA 19–21 clips 62 closure, ductus – anatomical 4 – functional 4 – rate 66, 84, 90 – surgical 57–60

CO2 monitor, end expiratory 58 colloidal fluids 58 comparison indomethacin and ibuprofen 65–68 compliance, lung 28 complications, operative 60–62 contracting factors 17 contraction regulation 7, 17 – phasic contraction 9 – tonic contraction 9 cortex, renal 70 corticosteroids, antenatal 17, 52 COX (cyclooxygenase) 12, 14, 74–83 – complications of COX inhibition 74–83 – pharmacology 12, 74–75 CP (cerebral palsy) 37, 70 creatinine concentration, serum 72, 78–79 cushions – intimal 2, 9 cyclooxygenase (see COX) 12, 14, 74–83 cytochrome P450 17 cytokines, proinflammatory 16

D developmental anatomy 2–5 dilating factors 17 Doppler – cerebral measurements 45–49, 71, 86 – color 40, 46 – flow measurements 46, 84 – mesenteric measurements 81 – parameters 45–46 – pulsed 42, 44 – range gate 86 – renal measurements 70, 78 ductus / ductal – anatomy 2–4 – diameter 86 – maturation (see there) 2–3 – shunt 41, 87

A–F

E echocardiography 19, 40–44, 89 embryogenesis 2 EMEA 92 encephalopathy, bilirubin 81 endothelial cell 17 endothelin 1 (ET1) 17 endothelium 4 enlargement – atrial 40, 86 – ventricular 40 enteral alimentation 31 enterocolitis, necrotizing (NEC) 31–34, 78 epidemiology 19–23

F fetal circulation 15–16 flow – alterations 46 – blood flow 33, 35–36, 40. 75–79, 85 – diastolic 45, 47, 81, 84 – Doppler measurements 45–49, 84 – patterns 46 – peak flow 89 – profile 40, 45 – rate 95 – reduced 84, 85 – shunt flow 40 – superior vena caval (SVC) flow 35, 86 – temporal mean 80 – velocity 40–41, 45, 49, 70–71, 88 – vena cava flow, superior 86 – volume flow 46, 48 fluid – excretion 60 – intake 52, 60 – parenteral fluids 58 formulation, intravenous 92 frequency of PDA 20

100

Subject Index

G gastrointestinal – abdominal side effects 71 – blood flow 74 – circulation 67 – hemorrhage 12, 74, 79 – hypoperfusion 31–34, 67 – perfusion 12, 70 glucocorticoid, antenatal 17, 52 glucose, blood sugar 58, 70–71

H half-life – ibuprofen 12, 65 – indomethacin 12 Hamburg ibuprofen study 54–55 hazy lungs 27 hearing impairment 82 heart defects, incidence 19 hemodynamics – cerebral hemodynamics 75 – relevance 40, 86 – renal hemodynamics 78 hemorrhage – abnormal bleeding 72 – cerebral / intraventricular 35–38, 75 – gastrointestinal 12, 74, 79 – intracranial 12, 35 – periventricular 36, 70, 72 – pulmonary 27–28 Heubner’s artery 45 hormone, antidiuretic (ADH) 70 hypertension, pulmonary 66, 78, 90 hypoperfusion – cerebral 85 – intestinal 31–34, 67, 78 hypoxia 31–32 – tissue hypoxia 31

I ibuprofen 54–56, 79, 85 – comparison indomethacin and ibuprofen 65–68 – half-life 12, 65 – Hamburg ibuprofen study 54–55 – NEC (necrotizing enterocolitis) 33 – properties of 65 – side effects 74-82 – structure ibuprofen lysine and THAM 65 icterus, bilirubin encephalopathy (kernicterus) 81 impairment – cerebral perfusion, 70 – hearing 82 – intestinal perfusion 31–34, 70 – neurodevelopmental 82 – neurosensory 70 – renal 70, 84 indomethacin 54, 69–72, 78 – comparison indomethacin and ibuprofen 65–68 – half-life 12 – NEC (necrotizing enterocolitis) 33, 70 – properties 70 – side effects 69–73 inflammatory response / pulmonary infection 26–27 – inflammatory mechanisms 32 infusion – bolus 71 – continuous 71 – saline 67 intensive care unit, neonatal 57–58 intervention, rate of 22, 85 intestinal (see also gastrointestinal) 12, 67, 70, 74 – perforation 33, 55, 71, 78 intimal cushions 2, 9 intracerebral hemorrhage 35–37, 52

intracranial – arteries 46–47 – hemorrhage 12, 35–37, 72 – pressure 48 ischemia, mesenteric 32, 67, 78 IVH (intraventricular hemorrhage) 35–38, 72 – subependymal germinal matrix 35

K K+ excretion, renal 70 kidney development (see also renal) 78 knockout mice, MHC 9

L LA / Ao ratio 43, 86 laryngeal nerve, left recurrent 60 left-to-right shunt 15, 44 lenticulostriate arteries 45 leukomalacia, periventricular (PVL) 37, 67 leukotrienes 13 lung – CLD (chronic lung disease) 28–29, 69 – fluid / lung water 16, 27–28 – maturity 35–36 – mechanics 28 LV (left ventricle) 43, 87 lymphatic clearance 28

M malformation, heart 19 management, perioperative 58 maturation, ductal 2–3 medulla, renal 70

101 Subject Index

mesenterial – artery 46, 79–81 – blood flow 33, 54, 79 – Doppler sonographic measurements 81 – ischemia 31, 67, 78 – perfusion 31–34, 67, 78 metabolism, prostaglandin 12–14 minute ventilation 29 mitral valve 89 MLC phosphorylation 9 muscle, smooth muscle – contraction 6–11 – relaxation 8, 17 – vascular smooth muscle cell 17 myeloperoxidase 27 myosin 6–7, 9 – light chain kinase 7

N NEC (necrotizing enterocolitis) 31–34, 53, 70 – ibuprofen 33 – indomethacin 33 – surgical ligation 34 necrosis 32 – enterocolitis, necrotizing (see NEC) 31–34, 52, 70 neonatal intensive care unit (see NICU) 57–58 nerve / nervus (N.) – N. recurrens 60, 63 – N. vagus 61 neurodevelopmental – outcome 62, 75, 85 neurosensory impairment 70, 82 neutrophils, activated 27 NICU (neonatal intensive care unit) 57–58 – preparation for operation in the NICU 58 nitric oxide (NO) 12, 17, 78

O O2 saturation 58, 78 operation (see also surgery) – complications 60–62 – perioperative management 58 – postoperative management 60 – preoperative positioning 59 – preparation for operation in NICU 58 – situs 61 – surgical management 58–60 – transport to operating room 57–58 organ – blood flow 74 – perfusion 46 outcome – digestive 79 – long-term 53, 62, 95 – neurodevelopmental 70, 75, 85 output – cardiac 15, 77 – urine 66, 72 – ventricular 75, 77, 87 oxygen / oxygenation – cerebral 67, 71, 74–75 – extraction 31 – fractional concentration of oxygen (FiO2) 78 – monitoring 58 – saturation 88 – supplemental 69 – tension 15, 17, 76 – tissue hypoxia 31

P palsy – CP (cerebral palsy) 37, 70 – phrenic palsy 63 – vocal palsy 60, 63 parenteral fluids 58 PCO2 58, 71, 75

G–P

PDA (persisting ductus arteriosus) 4 – asymptomatic 69 – definition 20 – incidence 21 – management, 52, 69 – prophylaxis of 69 – rate of PDA intervention 22, 85 – symptomatic 69, 85–90 – timing of PDA intervention 84–85 Pedea 92 perforation, intestinal 33, 55, 71, 79 perfusion – brain / cerebral 12, 46, 70–71, 85 – gastrointestinal 12, 70 – mesenteric 31–34, 67, 78 – organ 46, 74 – pulmonary 41 – renal 12, 67, 78 – systemic 41 periventricular – hemorrhage 35–37, 70, 72 – leukomalacia (PVL) 37, 67 persisting ductus arteriosus (see PDA) perspectives 94 PG synthesis 12–14, 71 PGDH (prostaglandin dehydrogenase) 14 PGE (see prostaglandin) 13–14, 78 pharyngeal arch 2–3 phasic contraction 9 phrenic palsy 63 platelets 54, 72 pleural drainage 60-62, 70 PO2, transcutaneous 58 positioning, preoperative 59 postnatal – circulation (see circulatory adaption) 15–18 pressure – blood pressure 60 – intracranial pressure 48 – pulmonary vascular pressure 88, 90

102

Subject Index

– right systolic ventricular pressure 88–89 – systemic systolic pressure 90 prevalence 19, 23 prostacyclin 12 – synthase / synthesis 13, 76 prostaglandin – metabolism 12–14, 94 – PGE2 (prostaglandin E2) 12–14 – PGDH (prostaglandin dehydrogenase) 14 – synthesis 78 pulmonary (see also respiratory) – artery 3, 41–42, 88–89 – blood flow 28, 75, 77 – bronchopulmonary dysplasia (BPD) 52 – cardiopulmonary adaptation 78 – circulation 40, 45 – hemorrhage 27–28 – hypertension 66, 78, 90 – immatury / surfactant deficiency 26 – infection / inflammatory response 26–27 – perfusion 41 – shunt, aorto-pulmonary 48 – valve 42, 86 – vascular pressure 88, 90 – vascular resistance 15, 75, 77, 81, 88 pulsatility index 31 PVL (periventricular leukomalacia) 37, 67

R radiant heaters 52 ratio, LA / Ao 43, 86 RBF (renal blood flow) 54, 70, 78 RDS (respiratory distress syndrome) 16, 20, 26 receptors, prostaglandin (see also PGE) 12–14 registration 92

regurgitation, tricuspid 88–89 relaxation, smooth muscle 8 renal – adverse renal effect 67 – artery / A. renalis 40, 70 – blood flow (RBF) 54, 70, 78 – cortex 70 – Doppler sonographic measurements 70, 78 – failure 70, 78 – function 54, 72, 78 – hemodynamics 78 – K+ excretion, renal 70 – perfusion 12, 70, 78 renin, plasma 70 research implications 94–97 resistance, vascular 15, 45, 71, 81 – cerebral 80 – index 46, 85 – peripheral vascular 45 – pulmonary vascular 15, 45, 75, 77, 88, 90 respiratory (see also pulmonary) – distress syndrome (RDS) 16, 20, 26 – failure 28 – problems 26–30 – right-to-left shunt 44, 88 root, aortic 40, 85 RSVP 88

S saline infusion 67 saturation, oxygen 88 septicemia 26 septum, interventricular 89 shunt / shunting 15 – aorto-pulmonary shunt 48 – bidirectional 44 – direction 88 – ductal shunt 41 – flow 40 – intra-cardiac 87 – left-to-right shunt 15, 44 – right-to-left shunt 15, 44, 88

side effects, abdominal 71 silent ductus 19 SM-MHC gene 8 smooth muscle – contraction 6–11 – relaxation 8, 17 – vascular smooth muscle cell 17 spectroscopy, near infrared 71 sternum / sternal – parasternal view 42 – suprasternal notch view 41 steroids, antenatal 17, 35, 52 surfactant – deficiency / pulmonary immaturity 26 – substitution 28 surgery / surgical (see also operation) – closure 57–64 – first line approach 22 – ligation, NEC 34 – management, surgical 58–60 – thoracoscopic 64 SVC (superior vena caval) flow 35, 86 systemic – circulation 40, 45 – inflammation 32 – perfusion 41

T temperature monitoring 58 THAM , structure of 65 thickening, intimal 3, 9 thoracic catheter 60 thoracoscopic surgery 64 thromboxane synthase 13 tidal volume 29 time averaged flow velocity 45, 49 tissue hypoxia 31 tonic contraction 9 transitional circulation 15 transport to operating room 57–58

103 Subject Index

tricuspid regurgitation 44, 88–89 truncus – arteriosus communis 48 – coeliacus 31, 40 twins 26

U urea nitrogen, blood 72 ureaplasma urealyticum 27 urine production / output 66, 72

V valve – aortic 42 – atrioventricular 42, 89 – mitral 89 – pulmonary 42, 86 – tricuspid 42, 89

vascular – endothelial growth factor (VEGF) 12 – resistance 15, 45, 71, 75, 88, 90 – smooth muscle cell 17 velocity – enddiastolic 31 – endsystolic 31 – flow velocity (see there) 33, 40–41, 45–49, 70–71, 89 – maximal systolic 32 – shortening 6 ventilation 28–29 – compliance 28 – minute ventilation 29 – tidal volume 29 ventricle / ventricular – atrioventricular valve 42, 89 – chambers 89 – dilation 9 – enlargement 40 – intraventricular hemorrhage (see IVH) 35–38, 72

R–X

– left (LV) 43, 89 – output 75, 77, 87 – periventricular hemorrhage 35, 70, 72 – right systolic ventricular pressure 88 – right (RV) 89 – septum, intraventricular 89 view, echocardiographic – long-axis 43 – parasternal 42 – short-axis 44 – suprasternal notch 41 volume – cerebral blood volume 67, 75 – flow 46, 48 – overload 84 – tidal 29

X X-ray opacities 27